Computational Analysis of the Regulation of EGFR by Protein Tyrosine Phosphatases

AbstractThe tyrosine phosphorylated epidermal growth factor receptor (EGFR) initiates numerous cell signaling pathways. Although EGFR phosphorylation levels are ultimately determined by the balance of receptor kinase and protein tyrosine phosphatase (PTP) activities, the kinetics of EGFR dephosphorylation are not well understood. Previous models of EGFR signaling have generally neglected PTP activity or computed PTP activity by considering data that do not fully reveal the kinetics and compartmentalization of EGFR dephosphorylation. We developed a compartmentalized, mechanistic model to elucidate the kinetics of EGFR dephosphorylation and the coupling of this process to phosphorylation-dependent EGFR endocytosis. Model regression against data from HeLa cells for EGFR phosphorylation response to EGFR activation, PTP inhibition, and EGFR kinase inhibition led to the conclusion that EGFR dephosphorylation occurs at the plasma membrane and in the cell interior with a timescale that is smaller than that for ligand-mediated EGFR endocytosis. The model further predicted that sufficiently rapid dephosphorylation of EGFR at the plasma membrane could potentially impede EGFR endocytosis, consistent with recent experimental findings. Overall, our results suggest that PTPs regulate multiple receptor-level phenomena via their action at the plasma membrane and cell interior and point to new possibilities for targeting PTPs for modulation of EGFR dynamics

Supercritical storage of hydrogen and oxygen for mobile fuel cell space applications

This report discusses the modeling and preliminary design of a system for the supercritical storage of hydrogen and oxygen for mobile fuel cell space applications, including rovers, spacesuits, and construction equipment. This system must operate on both low and zero gravity space missions requiring all reactant storage to be as a single phase to avoid sloshing while maintaining high storage efficiency. The purpose of this study is to develop a tank design for both fuel cell reactants, quantify heat duties throughout preparation and operation, and determine the optimal storage conditions. In addition, a preliminary schematic and control system for the system is developed based on the theoretical model. This study confirms that such a system is indeed plausible and could conceivably power the next generation of Lunar and Martian exploration. It was determined that the heat duties required to maintain the supercritical system are manageable, meaning the system is entirely feasible. Additionally, the system can be designed safely and efficiently within the stringent mass and volume constraints

Wind Power Suitability in Worcester, Massachusetts

The goal of this project was to identify criteria needed to determine the suitability of potential wind turbine sites in Worcester, Massachusetts. The report first discusses physical, environmental, economic, and social factors that affect the suitability of potential wind power sites. We then completed a case study for a site in downtown Worcester, directly applying the criteria. Our hope is the project will raise local awareness of renewable energy and illustrate the practicality of a clean energy project

Reactivation of ERK Signaling Causes Resistance to EGFR Kinase Inhibitors

The clinical efficacy of EGFR kinase inhibitors is limited by the development of drug resistance. The irreversible EGFR kinase inhibitor WZ4002 is effective against the most common mechanism of drug resistance mediated by the EGFR T790M mutation. Here we show, in multiple complementary models, that resistance to WZ4002 develops through aberrant activation of ERK signaling caused by either an amplification of MAPK1 or by downregulation of negative regulators of ERK signaling. Inhibition of MEK or ERK restores sensitivity to WZ4002 and prevents the emergence of drug resistance. We further identify MAPK1 amplification in an erlotinib resistant EGFR mutant NSCLC patient. In addition, the WZ4002 resistant MAPK1 amplified cells also demonstrate an increase both in EGFR internalization and a decrease in sensitivity to cytotoxic chemotherapy. Our findings provide insights into mechanisms of drug resistance to EGFR kinase inhibitors and highlight rationale combination therapies that should be evaluated in clinical trials