Quantification of Short Term Signaling by the Epidermal Growth Factor Receptor

Abstract

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.

Integrin-mediated signalling through the MAP-kinase pathway

“…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].…”

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

“…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.…”

A unifying view of 21st century systems biology

“…Modeling regulatory circuits [29][30][31] and larger scale networks [32,33], reconstructing metabolic networks [34], investigating network robustness [35,36] and stochastic gene expression in biological systems [37], were among the necessary conditions for a full reemergence of systems biology.…”