ERK activation by integrin-mediated adhesion: A computational and experimental study
Activation of the MAP kinase ERK is a key regulator of cell processes involved in tumorigenic behavior, such as proliferation and motility. In fact, the Ras/Raf/ERK pathway is up-regulated in many metastatic cell types. ERK may be activated by adhesion and growth factors separately and in combination. In combination, adhesion and growth factors stimulate sustained ERK activation, while independent activation by these factors is transient. The ability of adhesion and growth factor to modulate the dynamics of ERK activation is important because ERK activation magnitude and duration are key parameters in regulating cell behavior, particularly cell cycle progression. In this dissertation, a deterministic model of adhesion-mediated ERK activation via integrins is presented. With this model, we explore the role of adhesion in regulating ERK activation dynamics. In addition, key parameters regulating ERK activation dynamics are identified. To further focus on the role of integrins in mediating extracellular signals to intracellular signal transduction pathways, a detailed model of focal adhesion assembly is also developed. The mechanism and dynamics of focal adhesion assembly are also considered in a series of studies identifying system requirements for cluster formation and growth. Lastly, model predictions are verified with experiments in MCF10Aα5GFP mammary epithelial cells. Time courses of FAK and ERK specific activity in response to cell plating on fibronectin density are measured and confirm the simulation results. Moreover, a possible positive feedback mechanism linking ERK to focal adhesion assembly is hypothesized. Quantitative measurements of cluster number and size in MCF10Aα5GFPs plated on several fibronectin densities are also taken. These results confirm the model predictions and provide additional insights into clustering dynamics. ^
Ka Lai Yee,
"ERK activation by integrin-mediated adhesion: A computational and experimental study"
(January 1, 2007).
Dissertations available from ProQuest.