NDLI: Investigating dynamics of inhibitory and feedback loops in ERK signalling using power-law models.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Vera, Julio Rath, Oliver Balsa-Canto, Eva Banga, Julio R. Kolch, Walter Wolkenhauer, Olaf
Description	Country affiliation: Germany Author Affiliation: Vera J ( Systems Biology and Bioinformatics Group, University of Rostock, 18051 Rostock, Germany.)
Abstract	The investigation of the structure and dynamics of signal transduction systems through data-based mathematical models in ordinary differential equations or other paradigms has proven to be a successful approach in recent times. Extending this concept, we here analysed the use of kinetic models based on power-law terms with non-integer kinetic orders in the validation of hypotheses concerning regulatory structures in signalling systems. We integrated pre-existent biological knowledge, hypotheses and experimental quantitative data into a power-law model to validate the existence of certain regulatory loops in the Ras/Raf-1/MEK/ERK pathway, a MAPK pathway involved in the transduction of mitogenic and differentiation signals. Towards this end, samples of a human mammary epithelial cell line (MCF-10A) were used to obtain time-series data, characterising the behaviour of the system after epidermal growth factor stimulation in different scenarios of expression for the critical players of the system regarding the investigated loops (e.g., the inhibitory protein RKIP). The mathematical model was calibrated using a computational procedure that included: analysis of structural identifiability, global ranking of parameters to detect the most sensitivity ones towards the experimental setup, model calibration using global optimization methods to find the parameter values that better fit the data, and practical identifiability analysis to estimate the confidence in the estimated values for the parameters. The obtained model was used to perform computational simulations concerning the role of the investigated regulatory loops in the time response of the signalling pathway. Our findings suggest that the special regularity in the structure of the power-law terms make them suitable for a data-based validation of regulatory loops in signalling pathways. The model-based analysis performed identified RKIP as an actual inhibitor of the activation of the ERK pathway, but also suggested the existence of an intense feedback-loop control of the pathway by the activated ERK that maybe responsible for the damped oscillations we saw in the fraction of activated MEK both in the experiments and simulations. In addition, the model analysis suggested that phosphorylation/deactivation of RKIP during the transient stimulation may have a significant effect on the signalling peaks of both MEK and ERK. This later result suggests that dynamic modulation of signal inhibitors during stimulation may be a regulatory mechanism in ERK signalling and other pathways.
File Format	HTM / HTML
ISSN	1742206X
Issue Number	11
Volume Number	6
e-ISSN	17422051
Journal	Molecular BioSystems
Language	English
Publisher	Royal Society of Chemistry
Publisher Date	2010-11-01
Publisher Place	Great Britain (UK)
Access Restriction	Subscribed
Subject Keyword	Discipline Molecular Biology Discipline Biochemistry Extracellular Signal-regulated Map Kinases Metabolism Feedback, Physiological Map Kinase Signaling System Models, Biological Calibration Cell Line Enzyme Activation Humans Mitogen-activated Protein Kinase Kinases Phosphatidylethanolamine Binding Protein Phosphorylation Journal Article
Content Type	Text
Resource Type	Article
Subject	Molecular Biology Biotechnology

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