Understanding general principles in receptor tyrosine kinase signaling through structural and functional studies

Ut Southwestern Medical Center, Dallas TX

Investigators

Abstract

Abstract Receptor tyrosine kinases (RTKs) are a large family of single-pass transmembrane cell surface receptors that play key roles in normal cellular processes and are linked with many human diseases. In general, the ligand binding to the extracellular region of RTKs induces receptor dimerizaƟon and acƟvaƟon, but many RTKs cannot be acƟvated simply by ligand-induced dimerizaƟon. In the past 5 years, my lab has performed extensive structural (cryo-EM) and funcƟonal invesƟgaƟons of several special RTKs, including the IR, IGF1R, IRR, c-MET, RET, and MuSK. Each of the RTK stories from my lab individually defines how an important RTK is acƟvated through a unique mechanism. However, many quesƟons regarding the acƟvaƟon and regulaƟon of RTKs remain unanswered. Firstly, to date, none of the cryo-EM structures were able to resolve a complete structure of any RTKs, due to the flexible linkages of the TM with both the ECD and ICD. Therefore, how the conformaƟonal changes are coupled between the extracellular, transmembrane and intracellular regions remain unclear. Secondly, some RTKs are capable of triggering disƟnct downstream pathways when acƟvated by different ligands. These issues of signaling specificity and biased agonism are criƟcal to RTK funcƟon in vivo, but are not understood in physical terms. Thirdly, many RTKs such as TAM, epidermal growth factor receptor (EGFR) and Eph receptors form large clusters upon acƟvaƟon, but the underlying mechanisms are poorly understood. Our future research will be centered on answering these quesƟons, in order to define the general working principles of RTKs. Our innovaƟve approach combines biochemistry, biophysics, cell biology, ligand engineering, and cryo-EM. Finally, understanding the structural basis for the RTK acƟvaƟon and regulaƟon will enable us to design new therapeuƟcs to treat diseases that are caused by malfuncƟons of RTKs.