Regulation of RasGRP1 protein in thymocyte development and peripheral T cells

Lymphocytes express two Ras guanine exchange factors (RasGEFs), Sos and RasGRP1, which can act in concert to activate the Ras-MEK-ERK pathway downstream of antigen receptor signaling. RasGRP1 is capable of priming Sos and is required for optimal Sos activation. Sos is incapable of compensating for loss of RasGRP1 in lymphocytes as RasGRP1-deficient mice fail to develop single positive thymocytes. Conversely, overexpression of RasGRP1 in the thymus leads to the development of thymomas. Since RasGRP1 exists in this critical position between immunodeficiency and oncogenesis, it is important to understand the mechanisms underlying the regulation of RasGRP1 protein levels and activity. My studies suggest that posttranslational modifications of RasGRP1 exist to limit RasGRP1 activity after antigen receptor stimulation. RasGRP1 appears to be monoubiquitinated and is phosphorylated in the basal state as well as upon TCR stimulation. Additionally, a hypomorphic allele of RasGRP1 (RasGRP1Anaef) leads to relatively normal thymocyte development in the context of a wildtype TCR repertoire, but a modest impairment in positive selection is revealed when a transgenic TCR is used. Surprisingly, mice expressing this allele have appear to have phenotypically activated T cells, produce anti-nuclear antibodies and have hypercellular spleens by the age of 12 weeks. It appears that RasGRP1 may play a role in negatively regulating TCR signaling that was previously unrecognized. Thus, RasGRP1 must be properly regulated to prevent autoimmunity as well. Further work examining RasGRP1 protein function and regulation is required to understand the possibility and implications pharmacological targeting of this critical RasGEF in the disease state