Dataset Information

Topological analysis of MAPK cascade for kinetic ErbB signaling.

ABSTRACT: Ligand-induced homo- and hetero-dimer formation of ErbB receptors results in different biological outcomes irrespective of recruitment and activation of similar effector proteins. Earlier experimental research indicated that cells expressing both EGFR (epidermal growth factor receptor) and the ErbB4 receptor (E1/4 cells) induced E1/4 cell-specific B-Raf activation and higher extracellular signal-regulated kinase (ERK) activation, followed by cellular transformation, than cells solely expressing EGFR (E1 cells) in Chinese hamster ovary (CHO) cells. Since our experimental data revealed the presence of positive feedback by ERK on upstream pathways, it was estimated that the cross-talk/feedback pathway structure of the Raf-MEK-ERK cascade might affect ERK activation dynamics in our cell system. To uncover the regulatory mechanism concerning the ERK dynamics, we used topological models and performed parameter estimation for all candidate structures that possessed ERK-mediated positive feedback regulation of Raf. The structure that reliably reproduced a series of experimental data regarding signal amplitude and duration of the signaling molecules was selected as a solution. We found that the pathway structure is characterized by ERK-mediated positive feedback regulation of B-Raf and B-Raf-mediated negative regulation of Raf-1. Steady-state analysis of the estimated structure indicated that the amplitude of Ras activity might critically affect ERK activity through ERK-B-Raf positive feedback coordination with sustained B-Raf activation in E1/4 cells. However, Rap1 that positively regulates B-Raf activity might be less effective concerning ERK and B-Raf activity. Furthermore, we investigated how such Ras activity in E1/4 cells can be regulated by EGFR/ErbB4 heterodimer-mediated signaling. From a sensitivity analysis of the detailed upstream model for Ras activation, we concluded that Ras activation dynamics is dominated by heterodimer-mediated signaling coordination with a large initial speed of dimerization when the concentration of the ErbB4 receptor is considerably high. Such characteristics of the signaling cause the preferential binding of the Grb2-SOS complex to heterodimer-mediated signaling molecules.

SUBMITTER: Nakakuki T

PROVIDER: S-EPMC2262155 | biostudies-literature | 2008 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Topological analysis of MAPK cascade for kinetic ErbB signaling.

Nakakuki Takashi T Yumoto Noriko N Naka Takashi T Shirouzu Mikako M Yokoyama Shigeyuki S Hatakeyama Mariko M

PloS one 20080312 3

Ligand-induced homo- and hetero-dimer formation of ErbB receptors results in different biological outcomes irrespective of recruitment and activation of similar effector proteins. Earlier experimental research indicated that cells expressing both EGFR (epidermal growth factor receptor) and the ErbB4 receptor (E1/4 cells) induced E1/4 cell-specific B-Raf activation and higher extracellular signal-regulated kinase (ERK) activation, followed by cellular transformation, than cells solely expressing ...[more]

PMID: 18335053

Similar Datasets

Project description:Cell growth critically depends on signalling pathways whose regulation is the focus of intense research. Without utilizing a priori knowledge of the relative importance of pathway components, we have applied in silico computational methods to the EGF-induced MAPK cascade. Specifically, we systematically perturbed the entire parameter space, including initial conditions, using a Monte Carlo approach, and investigate which protein components or kinetic reaction steps contribute to the differentiation of ERK responses. The model, based on previous work by Brightman and Fell (2000), is composed of 28 reactions, 27 protein molecules, and 48 parameters from both mass action and Michaelis-Menten kinetics. Our multi-parametric systems analysis confirms that Raf inactivation is one of the key steps regulating ERK responses to be either transient or sustained. Furthermore, the results of amplitude-differential ERK phosphorylations within the transient case are mainly attributed to the balance between activation and inactivation of Ras while duration-differential ERK responses for the sustained case are, in addition to Ras, markedly affected by dephospho-/phosphorylation of both MEK and ERK. Our sub-module perturbations showed that MEK and ERK's contribution to this differential ERK activation originates from fluctuations in intermediate pathway module components such as Ras and Raf, implicating a cooperative regulatory mode among the key components. The initial protein concentrations of corresponding reactions such as Ras, GAP, and Raf also influence the distinct signalling outputs of ERK activation. We then compare these results with those obtained from a single-parametric perturbation approach using an overall state sensitivity (OSS) analysis. The OSS findings indicate a more pronounced role of ERK's inhibitory feedback effect on catalysing the dissociation of the SOS complex. Both approaches reveal the presence of multiple specific reactions involved in the distinct dynamics of ERK responses and the cell fate decisions they trigger. This work adds a mechanistic insight of the contribution of key pathway components, thus may support the identification of biomarkers for pharmaceutical drug discovery processes.

Dataset Information

Topological analysis of MAPK cascade for kinetic ErbB signaling.

Publications

Topological analysis of MAPK cascade for kinetic ErbB signaling.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets