Chemical and Biological Engineering MS Thesis Defense by Mohammadreza Yasemi

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KOÇ UNIVERSITY

GRADUATE SCHOOL OF SCIENCES & ENGINEERING

CHEMICAL AND BIOLOGICAL ENGINEERING

MS THESIS DEFENSE BY MOHAMMADREZA YASEMI

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Title: Dynamic Modeling of ERK Signaling Pathway: Sensitivity, Bistability and Oscillations

Speaker: Mohammadreza Yasemi

Time: September 18th, 2017, 15:00

Place: ENG 127

Koç University

Rumeli Feneri Yolu

Sariyer, Istanbul

Thesis Committee Members:

Prof. Dr. Yaman Arkun (Advisor, Koc University)

Prof. Dr. Ozlem Keskin (Koc University)

Doç. Dr. Burak Alakent (Bogazici University)

Abstract:

Cell signaling is the process by which extracellular information is transmitted into the cell to perform biological functions. ERK signaling pathway controls several cellular processes such as cell growth, proliferation, and gene expression. Deregulation caused by Ras mutations leads to various types of cancers. ERK signaling is triggered by binding of ligands to epidermal growth factor receptors (EGFRs). Upon binding, EGFR becomes phosphorylated on its tyrosine residues. Adaptor protein Grb2 binds to the phosphorylated EGFR and afterwards forms the Grb2-SOS complex. Ras, which is a small GTP binding protein, interacts with this complex and transforms to its active conformation by exchanging GDP for GTP. Active Ras acts as a decisive switch which starts phosphorylation of MAPK cascade that consists of Raf/MEK/ERK signaling molecules. In the literature, there exist mathematical models built for the distinct parts of this pathway. However, this thesis combines several existing models and develops a thorough model of the system starting from the ligand binding step to the nuclear processes mediated by ERK. The model is derived from mass-action kinetics and conservation laws. Several feedback loops which are embedded in ERK signaling pathway were closely studied and the range of the parameters leading to specific responses were identified. In particular, feedback loops were added based on an intensive literature review for the purpose of justifying experimental observations or in some cases for the providing new hypotheses subject to further validation. The complete model comprises 46 ordinary differential equations, 17 algebraic equations and 143 parameters. The mathematical analysis techniques, i.e. bifurcation analysis, parameter sensitivity and dynamics simulation were applied to determine the dynamic characteristics and steady-state responses of the system. We showed that any mutations or alterations in the feedback loops strength can lead to the irreversible adverse effects ultimately resulting in disease states. We establish conditions under which bistability and oscillations emerge for this important pathway. Using our model, we generated new hypotheses that hopefully can pave the way for future experimental design and verification.