RTK DOMAINS AND RTK DIMERIZATION THERMODYNAMICS

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DESCRIPTION (provided by applicant): We will determine the contributions of the four receptor tyrosine kinase (RTK) domains to the energetics of RTK lateral dimerization. The six receptors chosen for this study, ErbB1, ErbB2, ErbB3, FGFR1, FGFR2, and FGFR3, have been linked to human pathologies. The contributions of the different domains in these six RTKs to the dimerization free energies are currently unknown, mainly due to experimental challenges in the study of full-length RTKs, and membrane proteins in general. Here we will use a novel experimental approach, based on quantitative FRET, which yields dimerization thermodynamics in plasma membranes derived from mammalian cells. The work proposed here is the first step towards comprehensive characterization of the interplay between the different RTK domains in signaling. It will provide basic knowledge regarding the role of the different domains in the dimerization process, and thus aid in the development of highly specific therapeutics which can be used to treat cancers and growth disorders. PUBLIC HEALTH RELEVANCE: RTK domains and RTK dimerization thermodynamics Narrative Many pathologies are believed to occur due to disregulation of ligand-independent RTK dimerization. Here we will gain insight into this process by determining the contributions of the four receptor tyrosine kinase (RTK) domains to the energetics of RTK dimerization. The proposed work will aid in the development of highly specific therapeutics that can be used to treat cancers and growth disorders.