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Light-mediated Reversible Modulation of the Mitogen-activated Protein Kinase Pathway during Cell Differentiation and Xenopus Embryonic Development
Published on: June 15, 2017
Investigating differential dynamics of the MAPK signaling cascade using a multi-parametric global sensitivity
Jeongah Yoon1, Thomas S Deisboeck
1Complex Biosystems Modeling Laboratory, Harvard-MIT (HST) Athinoula A Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America.
Plos One
|February 24, 2009
Summary
Computational analysis reveals key regulators of the Extracellular signal-Regulated Kinase (ERK) pathway. Raf inactivation and Ras dynamics control ERK response timing and amplitude, offering insights for drug discovery.
Area of Science:
- Systems Biology
- Computational Biology
- Cell Signalling
Background:
- Cell growth relies on signalling pathways, with precise regulation crucial for cellular functions.
- The Epidermal Growth Factor (EGF)-induced Mitogen-Activated Protein Kinase (MAPK) cascade is a key pathway extensively studied for its role in cell growth and differentiation.
Purpose of the Study:
- To computationally identify key protein components and kinetic steps regulating Extracellular signal-Regulated Kinase (ERK) responses.
- To differentiate between factors controlling transient versus sustained ERK activation using in silico methods.
Main Methods:
- Application of in silico computational methods, specifically a Monte Carlo approach, to systematically perturb the parameter space of the MAPK cascade model.
- Utilizing a model based on Brightman and Fell (2000) comprising 28 reactions, 27 protein molecules, and 48 parameters.
- Comparison of multi-parametric systems analysis with single-parametric perturbation using overall state sensitivity (OSS) analysis.
Main Results:
- Raf inactivation identified as a critical step for regulating transient or sustained ERK responses.
- Ras activation/inactivation balance primarily dictates amplitude differences in transient responses.
- MEK and ERK phosphorylation dynamics, influenced by Ras and Raf, significantly affect sustained ERK response duration.
- Initial concentrations of Ras, GAP, and Raf influence distinct ERK signalling outputs.
- OSS analysis highlighted ERK's feedback effect on SOS complex dissociation.
Conclusions:
- Multiple specific reactions and protein components critically influence distinct ERK dynamics and downstream cell fate decisions.
- This mechanistic insight into pathway component contributions can aid in identifying biomarkers for pharmaceutical drug discovery.
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