The Role of p120 RasGAP in T Cells and Lymphatics.

Abstract

ABSTRACT

THE ROLE OF p120 RasGAP IN T CELLS AND LYMPHATICS

by

Philip E. Lapinski

Chair: Philip D. King

Ras is an intracellular signaling molecule that regulates many cellular processes in eukaryotic cells. Ras is activated by a class of proteins known as guanine nucleotide exchange factors (GEFs) and inactivated by GTPase-activating-proteins (GAPs). In T cells of the vertebrate immune system, the identity of the GEFs that activate Ras is known. In contrast, less is known about which GAPs inactivate Ras in this cell type. To learn more about the role of p120 RasGAP (RASA1) in the inactivation of Ras in T cells, we have generated a conditional RASA1-deficient mouse model. Using this model we have confirmed the role of RASA1 as a negative regulator of Ras in T cells. RASA1 controls not only activation of T cells in response to stimulation, but also helps to maintain their numbers in the peripheral immune system. The same mouse model has allowed us to establish that RASA1 is essential for the maintenance of lymphatic channels in mice which are necessary for T cell circulation through lymphoid organs and to sites of inflammation. In summary, we have established that RASA1 functions as an important physiological regulator of T cell function in vertebrates at multiple levels.