Seeking the Biophysical Principles that Govern RTK Activation

Johns Hopkins University, Baltimore MD

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Abstract

? DESCRIPTION (provided by applicant): Receptor Tyrosine Kinases (RTKs) regulate cell growth, differentiation, and motility. Aberrant RTK signaling can lead to disease, and RTK-specific therapies are being sought. Yet, there is no consensus model of RTK signal transduction across the plasma membrane, and the lack of basic knowledge is a bottleneck in further development and improvement of RTK-specific therapies. Two models are most often discussed in the literature, the diffusion-based or canonical model, or the pre-formed dimer model, which differ in the absence and presence of unliganded dimers. Here we explore the novel concept that most RTKs follow a universal activation mechanism, with the difference rooted in the exact value of the unliganded dimerization constant, rather than the fundamental receptor behavior. To test this concept, here we will establish a methodology that, for the first time, allows quantitative RTK dimerization measurements for physiological expression levels. We will characterize the stability of several RTK unliganded dimers in native plasma membranes, and we will assess whether their behavior is described by the law of mass action. We will assess the ability of ligands to induce structural changes in the RTK dimers, independent of the exact values of the unliganded dimer stabilities, in accord with the idea of a universal model of RTK activation. A universal model will provide a unified framework for understanding the similarities and differences in RTK activity. It will help us transition from qualitative to quantitative understanding of RTK signal transduction with predictive power. In the long run, this basic knowledge will help the scientific community in the search for novel RTK-inhibitors that can be used to combats human cancers and growth disorders.