ASSEMBLY-FUNCTION RELATIONS IN SIGNAL TRANSDUCTION ACROSS THE PLASMA MEMBRANE

Proteins known as “receptor tyrosine kinases” (RTKs) mediate the transmission of information across the cellular membrane, and thus allow the cell to respond to extracellular signals. Intercellular communication is a fundamental process in multicellular organisms and its precision is crucial for the control of growth and development. Multiple extracellular ligands can interact with an RTK to promote different intracellular events. The research project seeks to obtain quantitative information about the signaling properties of a member of the RTK family in response to its different ligands. Highly quantitative biophysical methods will be used in an effort to understand how diverse extracellular signals are processed by this receptor to promote distinct events. In this project, graduate students will be trained in state-of-the-art fluorescence microscopy techniques and the educational experience of undergraduate students will be enhanced. In addition, broad outreach activities will be conducted benefiting young scientists. The first objective is to acquire the first comprehensive data set of ligand-specific efficacies, potencies, and signaling preferences for multiple responses of the epidermal growth factor receptor (EGFR) to its ligands. This will entail acquisition of dose response curves for a variety of biological responses, yielding information about the potencies, efficacies and preferences of the ligands when inducing these responses. The second objective is to perform the first comprehensive physical-chemical characterization of the self-association of EGFR in the plasma membrane in response to its ligands. EGFR ligand-specific oligomer sizes (orders) and stabilities, and ligand binding coefficients, will be measured. The third objective is to uncover currently unknown correlations between measurable physical parameters and measurable signaling outcomes. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.