Dataset Information

Hornberg2005 - MAPKsignalling

ABSTRACT: Hornberg2005 - MAPKsignalling Large model of the ERK signalling network. Results from this model were used to generate a simplified version of the network. This model is described in the article: Control of MAPK signalling: from complexity to what really matters. Hornberg JJ, Binder B, Bruggeman FJ, Schoeberl B, Heinrich R, Westerhoff HV. Oncogene 2005 Aug; 24(36): 5533-5542 Abstract: Oncogenesis results from changes in kinetics or in abundance of proteins in signal transduction networks. Recently, it was shown that control of signalling cannot reside in a single gene product, and might well be dispersed over many components. Which of the reactions in these complex networks are most important, and how can the existing molecular information be used to understand why particular genes are oncogenes whereas others are not? We implement a new method to help address such questions. We apply control analysis to a detailed kinetic model of the epidermal growth factor-induced mitogen-activated protein kinase network. We determine the control of each reaction with respect to three biologically relevant characteristics of the output of this network: the amplitude, duration and integrated output of the transient phosphorylation of extracellular signal-regulated kinase (ERK). We confirm that control is distributed, but far from randomly: a small proportion of reactions substantially control signalling. In particular, the activity of Raf is in control of all characteristics of the transient profile of ERK phosphorylation, which may clarify why Raf is an oncogene. Most reactions that really matter for one signalling characteristic are also important for the other characteristics. Our analysis also predicts the effects of mutations and changes in gene expression. This model is hosted on BioModels Database and identified by: BIOMD0000000667. To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

SUBMITTER: Vijayalakshmi Chelliah

PROVIDER: BIOMD0000000667 | BioModels | 2024-09-02

REPOSITORIES: BioModels

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Source:

			Action	DRS
	BIOMD0000000667?filename=BIOMD0000000667-biopax2.owl	Owl
	BIOMD0000000667?filename=BIOMD0000000667-biopax3.owl	Owl
	BIOMD0000000667?filename=BIOMD0000000667-matlab.m	Other
	BIOMD0000000667?filename=BIOMD0000000667.m	Other
	BIOMD0000000667?filename=BIOMD0000000667.ode	Other

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Publications

Control of MAPK signalling: from complexity to what really matters.

Hornberg Jorrit J JJ Binder Bernd B Bruggeman Frank J FJ Schoeberl Birgit B Heinrich Reinhart R Westerhoff Hans V HV

Oncogene 20050801 36

Oncogenesis results from changes in kinetics or in abundance of proteins in signal transduction networks. Recently, it was shown that control of signalling cannot reside in a single gene product, and might well be dispersed over many components. Which of the reactions in these complex networks are most important, and how can the existing molecular information be used to understand why particular genes are oncogenes whereas others are not? We implement a new method to help address such questions. ...[more]

PMID: 16007170

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Project description:About 50% of human malignancies exhibit unregulated signalling through the Ras-ERK1/2 (ERK) pathway, as a consequence of activating mutations in members of Ras and Raf families. However, the quest for alternative Ras-ERK pathway-directed therapies is desirable. Upon phosphorylation ERK dimerize. We had previously demonstrated that dimerization is essential for ERK extranuclear but not nuclear signaling. Furthermore, by molecular biology approaches, we showed that specifically inhibiting ERK extranuclear component, by impeding ERK dimerization, is sufficient for curtailing tumor progression. Here, we have identified a small molecule inhibitor for ERK dimerization in vitro and in vivo that, without affecting ERK phosphorylation, prevents tumorigenesis driven by Ras-ERK pathway oncogenes, both in cellular and animal models. Importantly, this compound is unaffected by resistance-acquisition processes that hamper “classical” Ras-ERK pathway inhibitors. Thus, ERK dimerization inhibitors provide the proof of principle for two novel concepts in cancer therapy: 1) The blockade of sublocalization-specific sub-signals, rather than total signals, as a means of effectively counteracting oncogenic Ras-ERK signaling. 2) Targeting regulatory protein-protein interactions such as dimerization, rather than catalytic activities, within a signaling route, as an approach for producing effective anti-tumoral agents. Strategies aimed at preventing aberrant flux through this route remain an attractive option for therapeutic intervention in cancer. In this respect, drugs inhibiting the kinase activities of BRaf and MEK have yielded promising results. A375p cells treated with10 μM of either DEL22379, SCH772984 or DMSO as a control for two hours. mRNA from A375p cells was extrated using RNeasy mini kit (Qiagen, Germany) according to the manufacturer's instructions. Cells were previously treated with10 μM of either DEL22379, SCH772984 or DMSO as a control for two hours.