Understanding Ras effector switching and roles of Ras>RalGEF>Ral in development

SUMMARY Ras is the most mutated oncoprotein and functions at the center of an evolutionarily conserved network of proteins mutated in the RASopathy spectrum of heritable developmental disorders. Certain facets of Ras biology, like signaling cascades downstream of the Raf and PI3K oncogenic effectors, are among the best studied and pharmacologically targeted signals in all of biology. Yet how Ras switches between different effectors and the roles of the oncogenic RalGEF>Ral effector during development are poorly understood due to paralog redundancy, technical limitations in more complex systems, and the roadblock of Ral using the exocyst complex as a signaling intermediary. Research in this laboratory focuses on understanding the composition, organizational principles, and functions of signal transduction networks in vivo. This proposal will support a series of projects to answer how Ras switches between effectors in different developmental contexts, explore unexpected signaling relationships with other characterized signaling cascades, untangle the apparently paradoxical relationship between Ral and the exocyst complex in signaling vs. exocytosis, and to identify and understand novel functions of RalGEF>Ral signaling in development and physiology, about which surprisingly little is known. The laboratory has developed several crucial technical advances to overcome barriers to progress in this field. The proposed projects build on the lab’s ability dissect complex webs of signal transduction using genetic principles, complemented by cell biological and biochemical approaches. The proposed research is reasonably expected to discover novel principles and components in signal transduction.