Analyzing the role of the Ras effector TJ1 in controlling chemotaxis in Dictyostelium discoideum

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Chemotaxis plays a central role in various biological processes such as cellular morphogenesis, innate immunity, inflammation, and metastasis of cancer cells. Cells respond to shallow extracellular gradients which become highly amplified intracellularly via the localized activation of Ras, Rap1, and PI3K resulting in F-actin polymerization at the leading edge. Ras is an important upstream activator of chemoattractant-mediated PI3K activity; however, genetic data indicate that there must be other Ras effectors regulating chemotaxis. The Firtel lab recently identified a new Ras effector TJ1, a member of the MRL (Mig10/RIAM/Lpd) family of adaptor proteins, which they have shown is required for proper chemotaxis. Through the use of cell biological and molecular genetic approaches, I propose to dissect the function and regulation of TJ1, to obtain greater insight into how Ras signalling controls chemotaxis. I will use biochemical approaches to identify the binding partners of TJ1 and employ mutational studies to dissect how TJ1 is regulated and functions. In addition, I will examine the role of TJ1 and Ras signalling in controlling the vectors of the forces that control cell movement.