Mapping the functional versatility and fragility of Ras GTPase signaling circuits through in vitro network reconstitution

摘要

Cells sense and respond to the world around them using signaling “circuits” made of proteins and other molecules, and when an important cell circuit breaks, diseases like cancer may arise. Much like with electrical circuits, a given set of molecular components can be used to build different signaling circuits that behave in different ways. However, unlike for electrical circuits we generally do not have design manuals that allow us to work out how a signaling circuit behaves based on the components it includes. Doing this would involve identifying all the molecular parts of a circuit, using them to build every possible circuit, and carefully measuring the associated behavior. A group of proteins called the Ras-superfamily GTPases are important controllers of cell behavior. To investigate the behavior of Ras GTPase signaling circuits, Coyle and Lim built up different circuits from their components and “watched” their behavior with a microscope. Analyzing these behaviors provided the information needed to produce a ‘design manual’ for programming Ras circuits. Coyle and Lim found that the makeup of a Ras signaling circuit strongly affects the timing, duration, shape and size of its output. This means that different cells can use the same core components in different ways to build circuits customized to their specific needs. Nonetheless, this versatility comes with a trade-off the circuits are fragile, and can break in many different ways to cause disease. In the future Coyle and Lim aim to build other types of important cellular signaling circuits from their component parts. Only by building these systems, turning them on and watching them run can we begin to understand how they actually perform and what they are capable of.