Optogenetic Activation of membrane receptors. Implications in Cancer Drug Screening and Parkinson’s Disease

September 19th, 2017 ÁLVARO INGLÉS-PRIETO Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna

Receptor tyrosine kinases (RTKs) are a large family of membrane receptors that sense growth factors and regulate a variety of cell behaviors in health and disease. We used an optogenetic approach to activate RTKs by low-intensity blue light. Specifically, we selected light-oxygen-voltage (LOV)-sensing domains for their ability to activate RTKs by light-activated dimerization. Incorporation of LOV domains resulted in robust activation of relevant RTKs and the induction of cellular signaling in human cells with high spatio-temporal precision. Furthermore, light faithfully mimicked complex mitogenic and morphogenic cell behavior induced by growth factors. Next, we used light-activated RTKs to create an optogenetics-assisted drug screening platform. Our “all optical" approach obviates the addition of chemical activators or reporters, and reduces the number of operational steps. We screened a small library of kinase inhibitors using this platform, and we found that tivozanib specifically blocks the ROS1 orphan receptor, which is critically involved in lung cancer. Finally, we applied our light-activated RTKs to optically manipulate cell signaling in vivo. We generated a light-based fly model to trigger proliferative behavior during development, and to rescue cellular degeneration in a Parkinson’s disease model. These results suggest that engineered light-activated receptors promise a fast and precise approach to control signaling in cells and living animals.

Tuesday, September 19, 2017, 12:00. ICFO Seminar Room

Hosted by Maria Garcia-Parajo