Seeking the Biophysical Principles that Govern RTK Activation

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PROJECT SUMMARY Receptor Tyrosine Kinases (RTKs) are single-pass transmembrane proteins that control cell growth, differentiation, motility, and metabolism. They are very promising drug targets, but the incomplete understanding of the activation mechanism of the RTKs in the membrane hinders the development of effective and safe therapies. This proposal is dedicated to the development of new methodologies that can quantify molecular interactions and can move the field forward. In Aim 1, we will develop a combined Number and Brightness (N&B) and Förster Resonance Energy Transfer (FRET) methodology that yields both the oligomer size and the dissociation constants for full length RTKs in live cells. In Aim 2, we will develop a fluorescence-based methodology that yields molecular ligand binding constants for full-length RTKs in live cells. Along with enabling the acquisition of new knowledge by the broad scientific community, the work in the aims will yield new insights into critical aspects of the signaling by the RTKs used in method development.