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A Microfluidics Approach for the Functional Investigation of Signaling Oscillations Governing Somitogenesis

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Dynamics and control of the ERK signaling pathway: Sensitivity, bistability, and oscillations

Yaman Arkun¹, Mohammadreza Yasemi¹

¹Department of Chemical and Biological Engineering, Koc University, Rumeli Feneri Yolu, Sariyer, Istanbul, Turkey.

|April 10, 2018

Abstract:

Cell signaling is the process by which extracellular information is transmitted into the cell to perform useful biological functions. The ERK (extracellular-signal-regulated kinase) signaling controls several cellular processes such as cell growth, proliferation, differentiation and apoptosis. The ERK signaling pathway considered in this work starts with an extracellular stimulus and ends with activated (double phosphorylated) ERK which gets translocated into the nucleus. We model and analyze this complex pathway by decomposing it into three functional subsystems. The first subsystem spans the initial part of the pathway from the extracellular growth factor to the formation of the SOS complex, ShC-Grb2-SOS. The second subsystem includes the activation of Ras which is mediated by the SOS complex. This is followed by the MAPK subsystem (or the Raf-MEK-ERK pathway) which produces the double phosphorylated ERK upon being activated by Ras. Although separate models exist in the literature at the subsystems level, a comprehensive model for the complete system including the important regulatory feedback loops is missing. Our dynamic model combines the existing subsystem models and studies their steady-state and dynamic interactions under feedback. We establish conditions under which bistability and oscillations exist for this important pathway. In particular, we show how the negative and positive feedback loops affect the dynamic characteristics that determine the cellular outcome.

Insights

This study models the ERK signaling pathway, revealing how feedback loops influence cell growth, proliferation, and apoptosis. The research establishes conditions for bistability and oscillations in this crucial cellular process.

Area of Science:

Molecular Biology
Systems Biology
Cellular Signaling

Background:

Cell signaling transmits extracellular information for biological functions.
The ERK (extracellular-signal-regulated kinase) pathway regulates cell growth, proliferation, differentiation, and apoptosis.
Existing models often focus on subsystems, lacking a comprehensive view of the complete ERK pathway with feedback.

Purpose of the Study:

To develop a comprehensive dynamic model of the ERK signaling pathway.
To analyze the steady-state and dynamic interactions within the pathway, including feedback loops.
To identify conditions leading to bistability and oscillations in ERK signaling.

Main Methods:

Decomposition of the ERK pathway into three functional subsystems: ShC-Grb2-SOS complex formation, Ras activation, and the Raf-MEK-ERK cascade.
Integration of existing subsystem models into a comprehensive dynamic model.
Analysis of steady-state and dynamic behaviors under feedback control.

Main Results:

The developed model integrates subsystem dynamics and regulatory feedback loops.
Conditions for the existence of bistability and oscillations within the ERK pathway were established.
The impact of negative and positive feedback loops on pathway dynamics and cellular outcomes was elucidated.

Conclusions:

A comprehensive dynamic model of the ERK pathway incorporating feedback loops has been developed.
Feedback mechanisms play a critical role in determining the pathway's dynamic characteristics, such as bistability and oscillations.
Understanding these dynamics is crucial for predicting cellular responses to extracellular stimuli.

Read full analysis

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