The role of the RasGRP protein family in lymphocyte development

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T cells are a population of white blood cells that patrol the body in search of invading microorganisms. During their development in an organ called the thymus, T cells mature through a well-defined and easily monitored series of stages culminating with their entry into the circulation. Because the pathway of T cell development is well-known, it is often used as a model system with which to understand the function and regulation of various signaling pathways that are crucial to many biological responses including growth, differentiation, survival and death. This research program focuses on understanding the regulation of a critically important signaling pathway called the Ras/MAPK pathway by a family of proteins, collectively called the RasGRP family, using early T cell development as a model system. In T cells and many other blood cells, two families of proteins are thought to activate the Ras/MAPK pathway; the RasGRP and the Sos families. While it is known that the Ras/MAPK pathway is activated during early T cell development, the contribution of RasGRP proteins and Sos proteins to Ras activation is unclear. Using cell culture with various inhibitors and mice deficient in RasGRP proteins, we will determine the interplay between RasGRPs and Sos at various stages of T cell development. Furthermore, we will examine the mechanisms by which the RasGRP proteins are regulated by expressing mutant RasGRP proteins in cells that are genetically deficient for RasGRPs. Collectively, these studies will shed light on to the regulation of Ras by RasGRP and Sos proteins in T cells that can be applied to other cell types and biological responses.