Dynamic Studies of Scaffold-dependent Mating Pathway in Yeast

The mating pathway in \emph{Saccharomyces cerevisiae} is one of the best understood signal transduction pathways in eukaryotes. It transmits the mating signal from plasma membrane into the nucleus through the G-protein coupled receptor and the mitogen-activated protein kinase (MAPK) cascade. According to the current understandings of the mating pathway, we construct a system of ordinary differential equations to describe the process. Our model is consistent with a wide range of experiments, indicating that it captures some main characteristics of the signal transduction along the pathway. Investigation with the model reveals that the shuttling of the scaffold protein and the dephosphorylation of kinases involved in the MAPK cascade cooperate to regulate the response upon pheromone induction and to help preserving the fidelity of the mating signaling. We explored factors affecting the dose-response curves of this pathway and found that both negative feedback and concentrations of the proteins involved in the MAPK cascade play crucial role. Contrary to some other MAPK systems where signaling sensitivity is being amplified successively along the cascade, here the mating signal is transmitted through the cascade in an almost linear fashion.Comment: 36 pages, 9 figure

Computational models on cell migration

Cell migration is one of the most intriguing areas in cell biology and has attracted many interdisciplinary studies. It is regulated by complex biochemical signaling networks and comprises many mechanical processes, including protrusion, adhesion, translocation of the cell body and retraction of the rear. This dissertation starts with the signaling pathway that senses external chemoattractant, specifically, the Ras pathway (Chapter 2). We found that the response of an activated Ras shows near perfect adaptation. We attempted to fit the results using mathematical models for the two possible simple network topologies that can provide perfect adaptation. Only one, the incoherent feedforward network, is able to accurately describe the experimental results. This analysis revealed that adaptation in this Ras pathway is achieved through the proportional activation of upstream components and not through negative feedback loops. From Chapter 3 to Chapter 5, we integrated chemical reactions inside the cell with the mechanical process of cell migration. In Chapter 3, we set up a framework, based on phase field method, to describe the cell shape and the chemical reactions in a moving cell. Under this framework, we developed a computational model on cell morphodynamics in Chapter 4. Our model incorporates the membrane bending force and the surface tension and enforces a constant area. Furthermore, it implements a cross linked actin filament field and an actin bundle field that are responsible for the protrusion and retraction forces, respectively. The model was successfully applied to fish keratocytes and Dictystelium cells. In Chapter 5, we studied the coupling between adhesion mechanism and actin flow in keratocytes. The adhesion mechanism incorporated both the gripping mode and the slipping mode. The model-predicted maps of actin flow, substrate stress and the alignment between the two are quantitatively consistent with experimental observations. Furthermore, we explored the phase diagram of cell migration by varying myosin II and adhesion strength. Our model suggested that the pattern of the actin flow inside the cell, the cell velocity and the cell shape are determined by the integration of actin polymerization, myosin contraction, the adhesion and membrane force