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  • ACTIVATION  (9)
  • 1
    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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  • 2
    Keywords: RECEPTOR ; CELLS ; GROWTH ; GROWTH-FACTOR ; CELL ; COMBINATION ; KINASE ; MODEL ; MODELS ; PATHWAY ; PATHWAYS ; NETWORK ; NETWORKS ; SUPPORT ; SYSTEM ; SYSTEMS ; PROTEIN ; PROTEINS ; cell line ; ACTIVATION ; COMPLEX ; RESPONSES ; COMPLEXES ; MECHANISM ; mechanisms ; BIOLOGY ; SUPPRESSION ; TARGET ; AMPLIFICATION ; HUMANS ; SIGNALING PATHWAY ; SIGNALING PATHWAYS ; systems biology ; pathology ; FEASIBILITY ; Ras ; EPIDERMAL-GROWTH-FACTOR ; signaling ; interaction ; SUBSTRATE ; LEVEL ; USA ; PHOSPHATASE ; POSITIVE FEEDBACK ; reproducibility of results ; Models,Biological ; SIGNALING NETWORK ; signaling networks ; ERK ACTIVATION ; growth factor ; Extracellular ; cellular response ; CELLULAR-RESPONSE ; EPIDERMAL-GROWTH ; Dose-Response Relationship,Drug ; *Systems Biology ; 1-Phosphatidylinositol 3-Kinase/antagonists & inhibitors ; Adaptor Proteins,Signal Transducing/metabolism ; Drug Synergism ; Enzyme Activation/drug effects ; Epidermal Growth Factor/*pharmacology ; GRB2 Adaptor Protein/metabolism ; Immunoprecipitation ; Insulin/*pharmacology ; Mitogen-Activated Protein Kinases/metabolism ; Mitogens/*pharmacology ; Phosphorylation/drug effects ; Protein Kinase Inhibitors/pharmacology ; Protein Tyrosine Phosphatase,Non-Receptor Type 11/metabolism ; ras Proteins/metabolism ; Signal Transduction/*drug effects ; src-Family Kinases/metabolism
    Abstract: Crosstalk mechanisms have not been studied as thoroughly as individual signaling pathways. We exploit experimental and computational approaches to reveal how a concordant interplay between the insulin and epidermal growth factor (EGF) signaling networks can potentiate mitogenic signaling. In HEK293 cells, insulin is a poor activator of the Ras/ERK (extracellular signal-regulated kinase) cascade, yet it enhances ERK activation by low EGF doses. We find that major crosstalk mechanisms that amplify ERK signaling are localized upstream of Ras and at the Ras/Raf level. Computational modeling unveils how critical network nodes, the adaptor proteins GAB1 and insulin receptor substrate (IRS), Src kinase, and phosphatase SHP2, convert insulin-induced increase in the phosphatidylinositol-3,4,5-triphosphate (PIP(3)) concentration into enhanced Ras/ERK activity. The model predicts and experiments confirm that insulin-induced amplification of mitogenic signaling is abolished by disrupting PIP(3)-mediated positive feedback via GAB1 and IRS. We demonstrate that GAB1 behaves as a non-linear amplifier of mitogenic responses and insulin endows EGF signaling with robustness to GAB1 suppression. Our results show the feasibility of using computational models to identify key target combinations and predict complex cellular responses to a mixture of external cues.
    Type of Publication: Journal article published
    PubMed ID: 19357636
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  • 3
    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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  • 4
    Keywords: APOPTOSIS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; IN-VITRO ; CELL ; CELL LUNG-CANCER ; Germany ; INHIBITION ; KINASE ; PATHWAY ; PATHWAYS ; VITRO ; GENERATION ; SYSTEM ; SYSTEMS ; GENE ; DIFFERENTIATION ; TRANSDUCTION ; NF-KAPPA-B ; ACTIVATION ; COMPLEX ; LIGAND ; RESPONSES ; COMPLEXES ; MECHANISM ; INDUCTION ; hepatocytes ; INTERVENTION ; mechanisms ; BIOLOGY ; PHOSPHORYLATION ; signal transduction ; SIGNAL ; culture ; TARGET ; MAP KINASE ; MOUSE ; STRESS ; SIGNAL-TRANSDUCTION ; BETA ; NF-kappa B ; beta-catenin ; RAT HEPATOCYTES ; TARGETS ; ESTABLISHMENT ; FAS-LIGAND ; glutathione-S-transferase ; CYTOKINE ; RE ; SYNTHETASE ; INCREASE ; secretion ; FAS ; REPORTER GENE ; FUNCTIONAL-CHARACTERIZATION ; function ; MAP ; EXTENT ; modelling ; regeneration ; regulatory mechanism ; PREDICT ; CRYOPRESERVED HEPATOCYTES ; DRUG-METABOLISM ; ENZYME-INDUCTION ; GP130 ; LIVER-REGENERATION ; MEDIATE APOPTOSIS ; Stat3
    Abstract: Complex cellular networks regulate regeneration, detoxification and differentiation of hepatocytes. By combining experimental data with mathematical modelling, systems biology holds great promises to elucidate the key regulatory mechanisms involved and predict targets for efficient intervention. For the generation of high-quality quantitative data suitable for mathematical modelling a standardised in vitro system is essential. Therefore the authors developed standard operating procedures for the preparation and cultivation of primary mouse hepatocytes. To reliably monitor the dynamic induction of signalling pathways, the authors established starvation conditions and evaluated the extent of starvation-associated stress by quantifying several metabolic functions of cultured primary hepatocytes, namely activities of glutathione-S-transferase, glutamine synthetase, CYP3A as well as secretion of lactate and urea into the culture medium. Establishment of constant metabolic activities after an initial decrease compared with freshly isolated hepatocytes showed that the cultured hepatocytes achieve a new equilibrium state that was not affected by our starving conditions. To verify the highly reproducible dynamic activation of signalling pathways in the in vitro system, the authors examined the JAK-STAT, SMAD, P13 kinase, MAP kinase, NF-kappa B and Wnt/beta-catenin signalling pathways. For the induction of gp130, JAK1 and STAT3 phosphorylation IL6 was used, whereas TGF beta was applied to activate the phosphorylation of SMAD1, SMAD2 and SMAD3. Both Akt/PKB and ERK1/2 phosphorylation were stimulated by the addition of hepatocyte growth factor. The time-dependent induction of a pool of signalling competent B-catenin was monitored in response to the inhibition of GSK3 beta. To analyse whether phosphorylation is actually leading to transcriptional responses, luciferase reporter gene constructs driven by multiple copies of TGF beta-responsive motives were applied, demonstrating a dose-dependent increase in luciferase activity. Moreover, the induction of apoptosis by the TNF-like cytokine Fas ligand was studied in the in vitro system. Thus, the mouse hepatocyte in vitro system provides an important basis for the generation of high-quality quantitative data under standardised cell culture conditions that is essential to elucidate critical hepatocellular functions by the systems biology approach
    Type of Publication: Journal article published
    PubMed ID: 17186705
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  • 5
    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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  • 6
    Keywords: EXPRESSION ; ACTIVATION ; BREAST-CANCER ; PROTEOMICS
    Abstract: Analysis of large-scale proteomic data sets requires specialized software tools, tailored toward the requirements of individual approaches. Here we introduce an extension of an open-source software solution for analyzing reverse phase protein array (RPPA) data. The R package RPPanalyzer was designed for data preprocessing followed by basic statistical analyses and proteomic data visualization. In this update, we merged relevant data preprocessing steps into a single user-friendly function and included a new method for background noise correction as well as new methods for noise estimation and averaging of replicates to transform data in such a way that they can be used as input for a new time course plotting function. We demonstrate the robustness of our enhanced RPPanalyzer platform by analyzing longitudinal RPPA data of MET receptor signaling upon stimulation with different hepatocyte growth factor concentrations.
    Type of Publication: Journal article published
    PubMed ID: 25209047
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  • 7
    Keywords: measurement ; RECEPTOR ; proliferation ; SURVIVAL ; CELL ; CELL-PROLIFERATION ; Germany ; INHIBITION ; KINASE ; MODEL ; MODELS ; PATHWAY ; PATHWAYS ; NETWORK ; NETWORKS ; SYSTEM ; SYSTEMS ; POPULATION ; GENE ; PROTEIN ; transcription ; DIFFERENTIATION ; TRANSDUCTION ; ACTIVATION ; COMPLEX ; COMPLEXES ; FAMILY ; DOMAIN ; CYCLE ; PHOSPHORYLATION ; TARGET ; IDENTIFICATION ; inactivation ; SIGNALING PATHWAY ; SIGNALING PATHWAYS ; NUCLEUS ; PARAMETERS ; POPULATIONS ; PREDICTION ; BEHAVIOR ; max ; ERYTHROPOIETIN RECEPTOR ; EXPORT SIGNAL ; STAT1
    Abstract: Considerable progress has been made in identifying the molecular composition of complex signaling networks controlling cell proliferation, differentiation, and survival. However, to discover general building principles and predict the dynamic behavior of signaling networks, it is necessary to develop quantitative models based on experimental observations. Here we report a mathematical model of the core module of the Janus family of kinases (JAK)-signal transducer and activator of transcription (STAT) signaling pathway based on time-resolved measurements of receptor and STAT5 phosphorylation. Applying the fitted model, we can determine the quantitative behavior of STAT5 populations not accessible to experimental measurement. By in silico investigations, we identify the parameters of nuclear shuttling as the most sensitive to perturbations and verify experimentally the model prediction that inhibition of nuclear export results in a reduced transcriptional yield. The model reveals that STAT5 undergoes rapid nucleocytoplasmic cycles, continuously coupling receptor activation and target gene transcription, thereby forming a remote sensor between nucleus and receptor. Thus, dynamic modeling of signaling pathways can promote functional understanding at the systems level
    Type of Publication: Journal article published
    PubMed ID: 12552139
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  • 8
    Keywords: RECEPTOR ; Germany ; MODEL ; MODELS ; PATHWAY ; PATHWAYS ; SYSTEM ; SYSTEMS ; GENE ; COMPONENTS ; ACTIVATION ; MECHANISM ; mechanisms ; TRANSPORT ; DISTRIBUTIONS ; IDENTIFICATION ; COMPONENT ; inactivation ; NUCLEUS ; STAT1 ; LEADS ; PROTEIN-TYROSINE-PHOSPHATASE ; bootstrap ; bootstrap testing procedure ; differential equations ; LIKELIHOOD RATIO TESTS ; model selection ; non-nested non-linear models ; signalling pathway
    Abstract: Cellular signalling pathways, mediating receptor activity to nuclear gene activation, are generally regarded as feed forward cascades. We analyse measured data of a partially observed signalling pathway and address the question of possible feed-back cycling of involved biochemical components between the nucleus and cytoplasm. First we address the question of cycling in general, starting from basic assumptions about the system. We reformulate the problem as a statistical test leading to likelihood ratio tests under non-standard conditions. We find that the modelling approach without cycling is rejected. Afterwards, to differentiate two different transport mechanisms within the nucleus, we derive the appropriate dynamical models which lead to two systems of ordinary differential equations. To compare both models we apply a statistical testing procedure that is based on bootstrap distributions: We find that one of both transport mechanisms leads to a dynamical model which is rejected whereas the other model is satisfactory
    Type of Publication: Journal article published
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  • 9
    Keywords: CANCER ; EXPRESSION ; Germany ; PATHWAY ; GENE ; LINES ; TRANSDUCTION ; ACTIVATION ; COMPLEX ; IDENTIFICATION ; MALIGNANCIES ; REED-STERNBERG CELLS ; systems biology ; JAK2 ; STAT5
    Abstract: Primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (cHL) share a frequent constitutive activation of Janus-activated kinase (JAK) / signal transducer and activator of transcription (STAT) signaling pathway. Due to complex non-linear relations within the pathway, key dynamic properties remained to be identified to predict possible strategies for intervention. We report the development of dynamic pathway models based on quantitative data collected on signaling components of JAK/STAT pathway in two lymphoma-derived cell lines, MedB-1 and L1236, representative of PMBL and cHL, respectively. We show that the amounts of STAT5 and STAT6 are higher whereas those of SHP1 are lower in the two lymphoma cell lines compared to normal B cells. Distinctively, L1236 cells harbor more JAK2 and less SHP1 molecules per cell than MedB-1 or control cells. In both lymphoma cell lines we observe interleukin-13 (IL13)-induced activation of interleukin-4 receptor alpha, JAK2 and STAT5, but not of STAT6. Genome-wide, 11 early and 16 sustained genes are up-regulated by IL13 in both lymphoma cell lines. Specifically, the known STAT-inducible negative regulators CISH and SOCS3 are up-regulated within 2 hours in MedB-1 but not in L1236 cells. Based on this detailed quantitative information we established two mathematical models, MedB-1 and L1236 model, able to describe the respective experimental data. Most of model parameters are identifiable and therefore the models are predictive. Sensitivity analysis of the model identifies six possible therapeutic targets able to reduce gene expression levels in L1236 cells and three in MedB-1. We experimentally confirm reduction in target gene expression in response to inhibition of STAT5 phosphorylation, thereby validating one of the predicted targets.
    Type of Publication: Journal article published
    PubMed ID: 21127196
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