RTK DOMAINS AND RTK DIMERIZATION THERMODYNAMICS

描述(申请人提供)：我们将确定四个受体酪氨酸激酶(RTK)结构域对RTK侧向二聚的能量学的贡献。本研究选择的六种受体ErbB1、ErbB2、ErbB3、FGFR1、FGFR2和FGFR3与人类病理有关。这六个RTK中不同结构域对二聚化自由能的贡献目前尚不清楚，主要是由于全长RTK和膜蛋白研究中的实验挑战。在这里，我们将使用一种新的实验方法，基于定量FRET，它在哺乳动物细胞的质膜中产生二聚化热力学。这里提出的工作是全面描述不同RTK结构域在信令中的相互作用的第一步。它将提供关于不同结构域在二聚化过程中的作用的基本知识，从而有助于开发可用于治疗癌症和生长障碍的高度特异的疗法。 公共卫生相关性：RTK结构域和RTK二聚化热力学叙述许多病理被认为是由于配体非依赖性RTK二聚化的失调所致。在这里，我们将通过确定四个受体酪氨酸激酶(RTK)结构域对RTK二聚化的能量学的贡献来深入了解这一过程。这项拟议的工作将有助于开发可用于治疗癌症和生长障碍的高度特异的疗法。

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.