Computational modeling of the dynamics of the MAP kinase cascade activated by surface and internalized EGF receptors

Schoeberl, Birgit; Eichler-Jonsson, Claudia; Gilles, Ernst Dieter; Ga, Müller

doi:10.1038/nbt0402-370

Cited by 856 publications

(842 citation statements)

References 44 publications

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“…Previously, quantitative computational simulation proved to support understanding of regulatory systems [5][6][7][8][9][10] , characterizing threshold properties and bistability 11,12 , characteristic times 13,14 and feedback effects 12,[15][16][17][18][19] . The model presented here comprises receptor stimulation, the HOG signaling pathway, activation of gene expression, adaptation of cellular metabolism, glycerol accumulation and a thermodynamic description of the control of volume and osmotic pressure.…”

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confidence: 99%

Integrative model of the response of yeast to osmotic shock

et al. 2005

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Integration of experimental studies with mathematical modeling allows insight into systems properties, prediction of perturbation effects and generation of hypotheses for further research. We present a comprehensive mathematical description of the cellular response of yeast to hyperosmotic shock. The model integrates a biochemical reaction network comprising receptor stimulation, mitogen-activated protein kinase cascade dynamics, activation of gene expression and adaptation of cellular metabolism with a thermodynamic description of volume regulation and osmotic pressure. Simulations agree well with experimental results obtained under different stress conditions or with specific mutants. The model is predictive since it suggests previously unrecognized features of the system with respect to osmolyte accumulation and feedback control, as confirmed with experiments. The mathematical description presented is a valuable tool for future studies on osmoregulation in yeast and-with appropriate modifications-other organisms. It also serves as a starting point for a comprehensive description of cellular signaling.Osmoregulation encompasses active processes with which cells monitor and adjust osmotic pressure and control shape, turgor and relative water content. Even individual cells in multicellular organisms respond to osmotic changes, and strategies of cellular adaptation are conserved from bacteria to human 1 . The yeast Saccharomyces cerevisiae is a suitable model system to study osmoregulation and a substantial amount of information is available on osmotic shockinduced signal transduction, control of gene expression and accumulation of osmolytes 2 .Osmoregulation is a homeostatic process, though commonly studied as a response to osmotic shock. Central to yeast osmotic adaptation is the high osmolarity glycerol (HOG) signaling system 2,3 (Fig. 1). S. cerevisiae monitors osmotic changes through the plasma membrane-localized sensor histidine kinase Sln1. Under ambient conditions, Sln1 is active and inhibits signaling. Upon loss of turgor pressure, Sln1 is inactivated 4 resulting in activation of a mitogen-activated protein (MAP) kinase cascade and phosphorylation of the MAP kinase Hog1. Active Hog1 accumulates in the nucleus where it affects gene expression. Two HOG target genes encode enzymes in glycerol production. Hence, activation of Hog1 stimulates the production of glycerol, which serves as an osmolyte to increase intracellular osmotic pressure. Glycerol accumulation is also controlled by rapid closing of the aquaglyceroporin Fps1, which is an osmolarity-regulated glycerol channel. Hog1 activation and Hog1-dependent transcriptional stimulation are transient processes, indicating rigorous feedback control. Several protein phosphatases are known as negative regulators of the pathway. Although the overall organization of the systems is well characterized, open questions concern the mechanisms underlying activation and deactivation of the system, feedback control and the causal relationship between different events in...

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confidence: 99%

Integrative model of the response of yeast to osmotic shock

et al. 2005

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“…Subsequent analyses of FAK and downstream signalling focus on the relative effects of different parameter values on kinetics and magnitude, so that the conclusions drawn are valid regardless of the specific phenomenological constants used. Initial protein concentrations were obtained from Schoeberl et al [17] and were varied over several orders of magnitude to explore their effects on signal dynamics. The constant concentrations of phosphatases were also estimated based on these initial values.…”

Section: Model Parametersmentioning

confidence: 99%

“…A basic model of the Shc -Grb2 -Sos-Ras pathway activated by EGF was described by Kholodenko et al [16]. A more comprehensive model of ERK activation in response to EGF stimulation has also been examined [17]. In that model, EGF receptor -ligand binding and dimerisation initiate the traditional Shc-Grb2 -Sos-Ras pathway that leads to the MAPK cascade.…”

Section: Introductionmentioning

confidence: 99%

Integrin-mediated signalling through the MAP-kinase pathway

2008

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The mitogen activated protein (MAP) kinase cascade, leading to extracellular-regulated kinase (ERK) activation, is a key regulator of cell growth and proliferation. The effects of ERK are mediated by differences in ERK signalling dynamics, including magnitude and duration. In vivo, ERK signalling is stimulated by both growth factors and adhesion signals. A model for adhesionmediated ERK activation is presented. Outputs of the model such as ERK and FAK activation, as well as responses to different ligand densities, are compared with published experimental data. The model then serves as a basis for understanding how adhesion may contribute to ERK signalling through changes in the dynamics of focal adhesion kinase activation. The main parameters influencing ERK are determined through screening analyses and parameter variation. With these parameters, key points in the pathway that give rise to changes in downstream signalling dynamics are identified. In particular, oncogenic Raf and Ras promote cell growth by increasing the magnitude and duration, respectively, of ERK activity. This material is posted here with permission of the IEEE. Such permission of the IEEE does not in any way imply IEEE endorsement of any of the University of Pennsylvania's products or services. Internal or personal use of this material is permitted. However, permission to reprint/republish this material for advertising or promotional purposes or for creating new collective works for resale or redistribution must be obtained from the IEEE by writing to pubs-permissions@ieee.org. By choosing to view this document, you agree to all provisions of the copyright laws protecting it.This journal article is available at ScholarlyCommons: http://repository.upenn.edu/be_papers/104Integrin-mediated signalling through the MAP-kinase pathway K.L. Yee, V.M. Weaver and D.A. HammerAbstract: The mitogen activated protein (MAP) kinase cascade, leading to extracellular-regulated kinase (ERK) activation, is a key regulator of cell growth and proliferation. The effects of ERK are mediated by differences in ERK signalling dynamics, including magnitude and duration. In vivo, ERK signalling is stimulated by both growth factors and adhesion signals. A model for adhesionmediated ERK activation is presented. Outputs of the model such as ERK and FAK activation, as well as responses to different ligand densities, are compared with published experimental data. The model then serves as a basis for understanding how adhesion may contribute to ERK signalling through changes in the dynamics of focal adhesion kinase activation. The main parameters influencing ERK are determined through screening analyses and parameter variation. With these parameters, key points in the pathway that give rise to changes in downstream signalling dynamics are identified. In particular, oncogenic Raf and Ras promote cell growth by increasing the magnitude and duration, respectively, of ERK activity.

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“…S1 and S2). Phosphorylation and docking reactions are modeled according to Kholodenko et al;37 the MAP kinase pathway reactions are modeled after Schoeberl et al; 57 Akt and PI3K activation are incorporated into the model as described in Brown et al 7 The similar parameterization and topology in these models allowed us to construct a consistent, stable, and comprehensive system with results in good agreement with published experimental data. 52 Seventeen of these reactions are novel to this work and represent enhanced molecular resolution and detail in EGFR activation, phosphorylation, and docking reactions ( Fig.…”

Section: Overall Summary Of Methodsmentioning

confidence: 90%

A Multiscale Computational Approach to Dissect Early Events in the Erb Family Receptor Mediated Activation, Differential Signaling, and Relevance to Oncogenic Transformations

et al. 2007

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Abstract-We describe a hierarchical multiscale computational approach based on molecular dynamics simulations, free energy-based molecular docking simulations, deterministic network-based kinetic modeling, and hybrid discrete/ continuum stochastic dynamics protocols to study the dimermediated receptor activation characteristics of the Erb family receptors, specifically the epidermal growth factor receptor (EGFR). Through these modeling approaches, we are able to extend the prior modeling of EGF-mediated signal transduction by considering specific EGFR tyrosine kinase (EGFRTK) docking interactions mediated by differential binding and phosphorylation of different C-terminal peptide tyrosines on the RTK tail. By modeling signal flows through branching pathways of the EGFRTK resolved on a molecular basis, we are able to transcribe the effects of molecular alterations in the receptor (e.g., mutant forms of the receptor) to differing kinetic behavior and downstream signaling response. Our molecular dynamics simulations show that the drug sensitizing mutation (L834R) of EGFR stabilizes the active conformation to make the system constitutively active. Docking simulations show preferential characteristics (for wildtype vs. mutant receptors) in inhibitor binding as well as preferential enhancement of phosphorylation of particular substrate tyrosines over others. We find that in comparison to the wildtype system, the L834R mutant RTK preferentially binds the inhibitor erlotinib, as well as preferentially phosphorylates the substrate tyrosine Y1068 but not Y1173. We predict that these molecular level changes result in preferential activation of the Akt signaling pathway in comparison to the Erk signaling pathway for cells with normal EGFR expression. For cells with EGFR over expression, the mutant over activates both Erk and Akt pathways, in comparison to wildtype. These results are consistent with qualitative experimental measurements reported in the literature. We discuss these consequences in light of how the network topology and signaling characteristics of altered (mutant) cell lines are shaped differently in relationship to native cell lines.

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Computational modeling of the dynamics of the MAP kinase cascade activated by surface and internalized EGF receptors

Cited by 856 publications

References 44 publications

Integrative model of the response of yeast to osmotic shock

Integrative model of the response of yeast to osmotic shock

Integrin-mediated signalling through the MAP-kinase pathway

A Multiscale Computational Approach to Dissect Early Events in the Erb Family Receptor Mediated Activation, Differential Signaling, and Relevance to Oncogenic Transformations

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