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Displaying: 3 Found: 69 Total: 69


Quantification of short term signaling by the epidermal growth factor receptor.


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Quantification of short term signaling by the epidermal growth factor receptor. 

Kholodenko BN, Demin OV, Moehren G, Hoek JBJ.

Biol. Chem. 1999 Oct; 274(42): 30169-30181

During the past decade, our knowledge of molecular mechanisms involved in growth factor signaling has proliferated almost explosively. However, the kinetics and control of information transfer through signaling networks remain poorly understood. This paper combines experimental kinetic analysis and computational modeling of the short term pattern of cellular responses to epidermal growth factor (EGF) in isolated hepatocytes. The experimental data show transient tyrosine phosphorylation of the EGF receptor (EGFR) and transient or sustained response patterns in multiple signaling proteins targeted by EGFR. Transient responses exhibit pronounced maxima, reached within 15-30 s of EGF stimulation and followed by a decline to relatively low (quasi-steady-state) levels. In contrast to earlier suggestions, we demonstrate that the experimentally observed transients can be accounted for without requiring receptor-mediated activation of specific tyrosine phosphatases, following EGF stimulation. The kinetic model predicts how the cellular response is controlled by the relative levels and activity states of signaling proteins and under what conditions activation patterns are transient or sustained. EGFR signaling patterns appear to be robust with respect to variations in many elemental rate constants within the range of experimentally measured values. On the other hand, we specify which changes in the kinetic scheme, rate constants, and total amounts of molecular factors involved are incompatible with the experimentally observed kinetics of signal transfer. Quantitation of signaling network responses to growth factors allows us to assess how cells process information controlling their growth and differentiation.

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Stortelder1997 - Thrombin Generation Amidolytic Activity


Description

Abstract:

This paper describes the mathematical modelling of a part of the blood coagulation mechanism. The model includes the activation of factor X by a purified enzyme from Russel's Viper Venom (RVV), factor V and prothrombin, and also comprises the inactivation of the products formed. In this study we assume that in principle the mechanism of the process is known. However, the exact structure of the mechanism is unknown, and the process still can be described by different mathematical models. These models are put to test by measuring their capacity to explain the course of thrombin generation as observed in plasma after recalcification in presence of RVV. The mechanism studied is mathematically modelled as a system of differential-algebraic equations (DAEs). Each candidate model contains some freedom, which is expressed in the model equations by the presence of unknown parameters. For example, reaction constants or initial concentrations are unknown. The goal of parameter estimation is to determine these unknown parameters in such a way that the theoretical (i.e., computed) results fit the experimental data within measurement accuracy and to judge which modifications of the chemical reaction scheme allow the best fit. We present results on model discrimination and estimation of reaction constants, which are hard to obtain in another way.

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Switching from simple to complex oscillations in calcium signaling.


Description

We present a new model for calcium oscillations based on experiments in hepatocytes. The model considers feedback inhibition on the initial agonist receptor complex by calcium and activated phospholipase C, as well as receptor type-dependent self-enhanced behavior of the activated G(alpha) subunit. It is able to show simple periodic oscillations and periodic bursting, and it is the first model to display chaotic bursting in response to agonist stimulations. Moreover, our model offers a possible explanation for the differences in dynamic behavior observed in response to different agonists in hepatocytes.

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